(AKR/JxDBA/2J)F1 and H-2 compatible AKR/Cu mice resist transplantation of spontaneous AKR/J lymphoma. Resistance correlates with the development of cell mediated lympholysis (CML) in vitro. A primary F1 anti-AKR CML response results in Thy positive effector cells which lyse normal or lymphoma cells, suggesting that parental rather than tumor antigens are involved. The results suggest that "Hh" antigens are expressed on, and play a role in rejection of, spontaneously arising lymphoma cells. In vitro CML response between AKR substrains occurs only after in vivo priming with normal or lymphoma cells. The secondary in vitro CML can be elicited with, and assayed on, normal or tumor cells. Although the only known antigenic difference between the AKR substrains is the Thy antigen, B and T cells are equally good as immunogens and targets. Thus, the CML response is not directed solely to the Thy antigen. This CML is H-2 restricted for responder, immunogen and target cells. The data suggest the existence of a minor H antigen linked to the Thy locus. The AKR substrains differ genetically only at a region of chromosome 9, express high titers of murine leukemia virus and have 80-90% incidence of spontaneous lymphoma, yet a limited and possibly definable antigenic modification results in rejection of the reciprocal strains lymphoma.